There is speculation that small GTPases could serve as effective therapeutic targets in multiple cancer types. For example, it may be possible to counteract the effects of KRAS mutations in pancreatic cancers by using a small molecule KRAS inhibitor; however the essential nature of Kras in mice suggests there may be mechanism-based toxicity to such inhibitors. Validating the therapeutic index of small GTPases is critical for identifying new drug targets and for understanding pathogenic mechanisms of specific cancers. However, small GTPases are challenging drug targets (although not necessarily impossible to target) there is less incentive to spend significant resources on such difficult targets if they have not been validated in disease models. We aim to address this issue by developing a scalable system for testing the in vitro and in vivo consequences of pharmacological inhibition of small GTPases. Our long-term goal is to determine whether small GTPases are effective therapeutic targets for specific diseases. As a first step towards this goal, we are focused on developing a set of tools that would enable us to determine whether pharmacological inhibition of KRAS has limited toxicity in mice. We propose to design small molecules that are capable of inhibiting an engineered mutant allele of KRAS. These allele-selective inhibitors will be designed to have ADME/PK suitable for use in animal models. If successful, this system could be extended to test the therapeutic benefit of pharmacological inhibition of other small GTPases. Ultimately, these results would determine which small GTPases serve as effective drug targets.